4-(tertiary-aminoalkanoylamino)-2-alkoxybenzoic acid derivatives and their preparation



Patented Oct. 27, 1953 D: smmes PATENT? ET- 4 EE MARX- A KANOYIAM NQ')-2 ALKQXXBENZQIQ ACID-DERWATWES. AND. THEIRPBEPABATION Raymond Clinton,North Greenbush, N; Y., assignomto sterlingi Drug- Inc., New York, -NY.-,- acorponationtofiDelaware qDrawi s pnlic npSent -18 l s rial, No.247,195.

25Claimsr= (Cl. 260*2943) This" invention relates to H-(tertiary-aminoalkanoylamino)2 alkoxyhenzoig acids, 'tO" de rivativesthereof and "to the preparation of these compounds.

The compoundsof my inventionhave the gem eral formula aiidth'elike; inthe ab'oveformula, the'lower 2 alkyl radicals designated as R2 'andBreach has prefe'rablyfrom one to six carbon atomsinclusive, includingsuch radicals as; methyl;- ethyl; npropyl, n-butyl, isobutyl,-- n-amyl,2-amy1-, nhexyl, and the like.

The compounds of "myinvention are prepared. preferably'aceording to theprocedur -illustrated as followsjwhere XyNRB Rg and 'Rz have-themeanings as definedabovez In step I, a: lower alkyl 4-amino-2-alkoxygorbenz yloxy) benzoatg (A); is treated with a halokanqy'l hal deql izz h ethe e -"a oms e c lorine bro in l i d ne a anbee same or difi erent toform a lower alkyl 4- (halo kannylamino e -a isox fio n xw benzo (C).Thellaloalkanoylaminqester (0) is-treated ns ep w thia' c nda m e ha eformula; I-INRR to yield the corresponding lower allgyl 4-('tertiaryaminoalkanoylamino) 2=slibstit ited+loenzoate (D-), Theytertiaryaminoalkanoylamino esterlD) isthen 'saponified in step II It0yieldthe'corresponding 4(teirtiaryaminoalkanoyiamino) 2"= substituted'benzoic acid (E) which, in step IV, is convertedginto the corresponding4-;(tertiary-aminoalkanoylaminofl-zealkoxy (011 benzyloxylbenzamide (F)As an example of this procedure, a lower; alkyl ester of 4=amino2-naprepoxybenzoic acid is treated with a haloacetyl halide, preferablych'loroaeetyl' (2'-chl'oro ethanoyl chloride;-- to f rm thecorresponding lower' alkyl 441124- acetylamino) -2-n'-,propoxyhenzoate"(C3 Treatment of this compound (C) with diethylami-neyieldsthecorrespondin'g lower alkyl 4'-('diethylaminoacetylamino')2-n-propoxybenzoate (Di;

Saponification of the ester (D) then results in the formation of thecorresponding 4-(diethylaminoacetylamino) 2 n propoxybenzoic acid (E),which is then converted, preferably through its acid chloride, into4-(diethylaminoacetylamino) -2-n-propoxybenzamide (F). Following thisprocedure but using compounds where R2 is benzyl, X is CH2CHzCH2-, thatis, where halogen-CO-X-halogen is a 4-halobutanoyl halide, and whereHNRR; is Z-methyl-l-piperidyl, the resulting products are a lower alkyl4-[4-(2-methyl l piperidyl)butanolylarninol- 2-benzyoxybenzoate (D), 4[4 (2-methyl-1- piperidyl)-butanoy1amino]-2-benzoic acid (E) and 4 [4 (2methyl-l-piperidyl)butanoylaminol-2-benzamide (F), respectively.

The lower alkyl 4-amino-2-alkoxybenzoates (A), where R2 is lower alkyl,are disclosed and claimed in the copending application Serial No.238,396, filed July 24, 1951.

The 4-(tertiary-aminoalkanoylamino) -2substituted-benzoic acids, estersand amides of my invention are therapeutically active or useful asintermediates whether employed in the form of their free bases or in theform of their salts with relatively non-toxic organic or inorganicacids. In practicing my invention I have found it convenient to isolatemy compounds in the form of their hydrochlorides. However, other acidaddition salts are within the scope of my invention. Such additionalsalts include the hydrobromides, sulfates, phosphates, citrates,sulfamates, tartrates, succinates, acetates, benzoates, cleates, and thelike.

The following examples illustrate further specific embodiments of myinvention.

1. Lower alkyl 4-a1m'no-2-b6n2ylox11ben2odtcs acceptor. Thesepreparations are illustrated by the following examples.

Ethyl 4-nitro-2-benzyloxybenzoate was prepared as follows: A mixture of21.1 g. of ethyl 4-nitro-2-hydroxybenzoate, 13.9 g. of benzyl chloride,7.4 g. of anhydrous sodium carbonate, 5

100 ml. of ethanol, 0.4 m1. of water and 1.7 g. of potassium iodide wasrefluxed with vigorous stirring on a steam bath for four and one-halfhours. The reaction mixture was filtered while hot and the filtrate wascooled well in ice. A first crop of a white cottony precipitate wascollected. A second crop, which was obtained by diluting the filtratewith two volumes of ice and water, was filtered and the combined cropswere recrystallized three times from absolute ethanol, yielding 25 g.(83%) of ethyl 4-nitro-2-benzyloxybenzoate, M. P. 57.0-58.5" C. (cor.).

AnaZ.-Calcd. for C16H15NO5INNO2, 4.65. Found: Nno 4.57.

When the above procedure is followed but using, in place of ethyl4-m'tro-2-hydroxybenzoate, the corresponding methyl 4-nitro-2-hydroxybenzoate, n-propyl 4-nitro-2-hydroxybenzoate, n-butyl4-nitro-2-hydroxybenzoate, isobutyl 4 nitro- 2 hydroxybenzoate, n-amyl4-nitro-2-hydroxybenzoate or n-hexyl 4-nitro-2- hydroxybenzoate, thereis obtained, respectively, methyl 4-nitro 2 benzyloxybenzoate, n-propyl4-nitro-2-benzyloxybenzoate, n-butyl 4-nitro-2- benzyloxybenzoate,isobutyl 4-nitro-2-benzyloxy 4 benzoate, n-amyl4-nitro-2-benzyloxybenzoate or n-hexyl 4-nitro-2-benzyloxybenzoate.

Ethyl 4-amino-2-benzyloxybenzoate was prepared. as follows: To a stirredboiling mixture of of powdered iron, 800 ml. of ethanol, 300 ml. ofwater and 1 ml. of concentrated hydrochloric acid was added in smallportions 105.1 g. of ethyl 4 nitro 2 benzyloxybenzoate. The source ofheat was removed during this addition. After completion of theexothermic addition, the mixture was stirred and boiled gently fortwenty minutes, cautiously treated with 30 g. of powdered sodiumbicarbonate and stirred at the boiling point for ten minutes more. Thehot mixture was filtered through a pad of a filter aid and the insolublematerial was thoroughly washed with hot ethanol. The ethanol was removedfrom the combined filtrates in vacuo and the resulting solid residue wasdiluted with ice and water, filtered, washed with water andrecrystallized from benzene-n-hexane. There was thus obtained 93.0 g. ofethyl 4-amino-2-benzyloxybenzoate. M. P. 126-1265" C.

Following the above procedure but using, in place of ethyl4-nitro-2-benzyloxybenzoate, the corresponding methyl4-nitro-2-benzyloxybenzoate, n-propyl 4-nitro 2 benzyloxybenzoate,n-butyl 4-nitro 2 benzyloxybenzoate, isobutyl4-nitro-2-benzyloxybenzoate, n-amyl 4-nitro-2- benzyloxybenzoate orn-hexyl 4-nitro-2-benzyloxybenzoate, there is obtained, respectively,methyl 4-amino-2-benzyloxybenzoate, n-propyl4-amino-2-benzyloxybenzoate, n-butyl 4-amino- 2-benzyloxybenzoate,isobutyl 4-amino-2-benzyloxybenzoate, n-amyl 4-amino-2-benzyloxybenzoateor n-hexyl 4-amino-2-benzyloxybenzoate.

2. lower alkyl -(haloalkanoylamino)-2-aZ7cozry- (and -benzylo:ry)benzoates These compounds are prepared by treating the correspondinglower alkyl 4-amino-2-alkoxybenzoates or lower alkyl4-amino-2-benzyloxybenzoates with a haloalkanoyl chloride. The followingexamples are illustrative.

Ethyl 4- (chloroacetylamino) -2-ethoxybenzoate was prepared as follows:To a solution of 20.9 g. of ethyl 4-amino-2-ethoxybenzoate in 250 ml. ofdry benzene was added 12.4 g. of chloroacetyl chloride, thereby yieldinga semi-gelatinous precipitate. The reaction mixture was refluxed slowlyfor three and one-half hours, hydrogen chloride being evolved vigorouslyat initial reflux. Most of the benzene was removed by distilling invacuo and the product was precipitated by adding n-hexane. Theprecipitate was collected and recrystallized twice from benzene-nhexane,the second time with decolorization, thereby yielding, as rosettes oflarge white prisms, ethyl 4 (chloroacetylamino) -2-ethoxybenzoate, M. P.1l2.8-1l3.8 C. (cor.) when dried in vacuo at 60 C. for seven hours.

AnaZ.Calcd. for C13H16ClNO4: C, 54.64; H, 5.65; N, 4.90. Found: C,54.47; H, 5.38; N, 4.91.

Following the above procedure but using methyl 4-amino-2-ethoxybenzoate,n-butyl 4-amino-2- ethoxybenzoate or n-hexyl 4-amino-2-ethoxybenzoate inplace of ethyl 4-amino-2-ethoxybenzoate, there is obtained,respectively, methyl 4' (chloroacetylamino) 2 ethoxybenzoate, n-butyl 4-(chloroacetylamino) -2-ethoxybenzoate or n-hexyl 4-(chloroacetylamino)-2-ethoxybenzoate. When the above procedure is followed but using,instead of chloroacetyl chloride, bromoacetyl bromide, 3 4chloropropanoyl chloride, 4c'hlorobutanoyl chloride or4-chloro-2-methylcrystallizations of yielded, as white toxybenzoate wasprepared following the procedure described above for the preparation ofethyl '4-(diethylaminoacetylamino) 2 ethoxybenzoate but using 41.0 g. ofethyl 4- (chloroacetylamino) -2-n-butoxybenzoate, 20.0 g. ofdiethylamine and 300 ml. of absolute ethanol, and a reflux period ofeight hours. The product, in free base form, was obtained as a mobileoil. The product in the form of its hydrochloric acid addition saltmelted at 133.0-134.4 C. (cor) when recrystallized twice from. ethylacetate-ether.

AnaZ.--Calcd. for C19H30NzO-4.HC1I N. 7.24; Cl, 9.16. Found: N, 7.23;01, 9.30.

Ethyl 4- (2-methyl-1-piperidyl) acetylaminol 2-n-butoxybenzoate wasprepared following the foregoing procedures but using 13.0 g. of ethyl-4 (4 chloroacetylamino) 2 n butoxybenzoate, 8.6 g. of2-methylpiperidine and 200 ml. of

absolute ethanol, and a reflux period of eight hours. The product wasobtained as a viscous readily crystallized. Two rethis material fromn-heptane prisms, ethyl 4-[(2-methyl-1- piperidyl) acetylaminolZ-n-butoxybenzoate, in free base form, M. P. 70.2-71.8" C. (cor.).

AnaZ.--Calcd. for Call-132N204: N, 7.46. Found: N, 7.52.

Ethyl 4 [(2-methyl l pi'peridyDacetylamino]-2-n-butoxybenzoate in theform of its yellow oil which hydrochloride salt melted at 1861-1871 C.(con).

AnaZ.-Calcd. for C21Ha2N2O4.HC1Z N, 6.78; Cl, 8.59. Found: N, 6.99; Cl,8.82.

When the above procedures are followed but using the appropriate loweralkyl 4-(haloacetylamino) 2-alkoxybenzoate and the appropriate secondaryamine, there is obtained the following compounds: methyl 4 [(1piperidyl)acetylamino] 2 n-propoxybenzoate; methyl 4 [(1 pyrrolidyl)acetylaminol 2 n butoxybenzoate; n-propyl 4-[ (2-methyl-1-pyrrolidyl)-acetylamino]-2-n-propoxybenzoate; n-butyl 4[(2,=- dimethyl 1pyrrolidyl) acetylaminol-2-nbutoxybenzoate; isobutyl4-[(2,6-dimethyl-lpiperidyl) acetylamino] 2 isobutoxybenzoate; n hexyl 4[(4 morpholinyl) acetylaminol- 2-n-hexoxybenzoate; n-butyl 4-(di-n-butylaminoacetylamino) -2-methoxybenzoate; ethyl4-(dimethylaminoacetylamino) 2 isobutoxybenzoate; and ethyl4-[(1piperidyl)acetylaminol-2- n-hexoxybenzoate.

Ethyl 4- (diethylaminoacetylamino) -2-benzyloxybenzoate was preparedfollowing the procedure described above but using 50.0 g. of ethyl 4-(chloroacetylamino) -2-benzyloxybenzoate, 21.2 g. of diethylamine and309 ml. of absolute ethanol, and a reflux period of eight hours. Theproduct was obtained as a mobile, pale orange oil. In the form of itshydrochloride salt this ester melted at 1l9.8-12l.4 C. (c012) whenrecrystallized from isopropanol-ethyl acetate.

AnaZ.-Calcd. for CzzI-IzsNzOLI-ICI: N, 6.66; Cl,-

'8.42. Found: N, 6.68; Cl, 8.14. a

When the above procedure is followed but using, in place of ethyl4-(chloroacetylamino) -2- benzyloxybenzoate, the corresponding methyl 4-(chloroacetylamino) 2 benzyloxybenzoate, n-- propyl 4(chloroacetylamino) 2 benzyloxybenzoate, n-butyl 4-(chloroacetylamino)-2- benzyloxybenzoate, isobutyl 4 (chloroacetylamino)-2-benzyloxybenzoate, n-amyl 4-(chloroacetylamino) 2-benzyloxybenzoateor n-hexyl 4- (chloroacetylamino) -2-benzyloxybenzoate, there isobtained respectively the corresponding methyl 4(diethylaminoacetylamino) 2 benzyloxybenzoate, n-propy .4-(diethylammoacetylamino) 2-benzyloxybenzoate, n-butyl4-(diethylaminoacetylamino)-2-benzyloxybenzoate, isobutyl 4-(di-ethylaminoacetylamino) -2 benzyloxybenzoate, n amyl4-(diethylaminoacetylamino) -2- benzyloxybenzoate or n-hexyl4-(diethylaminoacetylamino) -2-benzyloxybenzoate.

Ethyl 4- (2-methyl-1-piperidyl) acetylaminol Z-benzyloxybenzoate wasobtained, in free base form, as a viscous pale yellow oil, when theabove procedure was followed'but using 14.4 g. of ethyl 4(chloroacetylamino) 2 benzyloxybenzoate, 8.6 g. of 2-methy1piperidineand 200 ml. of absolute ethanol, and a reflux period of eight hours.

Ethyl 4- (Z-methyl-l-piperidyl) -acetylaminol 2-benzyloxybenzoate, inthe form of its hydrochloric acid addition salt melted at 1696-1710 C.cor.) when recrystallized twice from absolute ethanol.

AnaZ.--Calcd. for C24H30N2O4.HC1Z N, 6.27; Cl, 7.93. Found: N, 6.32; Cl,7.90.

When the above procedure is followed but using, in place of ethyl4-(chloroacetylamino) -2- benzyloxybenzoate, ethyl 4-(bromoacetylamino)-2-benzyloxybenzoate, ethyl 4-(S-chloropropanoylamino)-2-benzyloxybenzoate or ethyl4-(4-chloro-3-methylbutanoylamino) 2 benzyloxybenzoate and using, inplace of 2-methylpiperidine, piperidine, pyrrolidine or morpholine,respectively, there is obtained ethyl 4-[(1-piperidyl) acetylamino]-2-benzyloxybenzoate, ethyl 4- [3- (l-pyrrolidyDpropanoylaminol 2benzyloxybenzoate or ethyl 4- [4- (4-morpholinyl)-3-methylbutanoylamino]-2-benzyloxybenzoate, respectively.

4. 4- (tertiary-aminoalkanoylamino) -2-alkoxy- (and -ben.zylo:cy)benzoicacids ..hese compounds are prepared by treating the corresponding loweralkyl 4-(tertiary-aminoalkanoylamino) -2-substituted-benzoates with analkaline sapcnifying agent, such as potassium hydroxide, sodiumhydroxide or sodium carbonate. This saponification is illustrated by thefollowing examples.

4 (diethylaminoacetylamino) -2-ethoxybenzoic acid was prepared asfollows: A mixture containing 6.4 g. of ethyl4-(diethylaminoacetylamino)- 2-ethoxybenzoate, 1.7 g. of potassiumhydroxide, 25 m1. of water and 50 ml. of ethanol was refluxed for onehour. The ethanol was removed from the resulting clear pale yellowsolution by distilling in vacuo, and the remaining solution wasacidified with concentrated hydrochloric acid and saturated with sodiumchloride, where upon there separated an oily precipitate which readilycrystallized. The mixture was cooled well in ice and the precipitatecollected. This prodnot, 4 (diethylarninoacetylarnino) -2ethoxybenzoicacid hydrochloride, melted at 203.6-204.1 C. (con) with decompositionwhen recrystallized once from absolute ethanol and once from absoluteethanol-isoprcpanol.

AnaL-Calcd. fOl C15I'I2 2N20 HC1: Found: Cl, 10.64.

4 (diethylaminoacetylamino) -2ethoxybenzoic acid is also obtainedfollowing the foregoing procedure but using, in place of ethyl4-(diethylaminoacetylamino)-2-ethoxybenzoate, the cor responding methyl4- (diethylaminoacetylamino) Z-ethoxybenzoate, n-butyl4-(diethylaminoacetylamino) -2-ethoxybenzoate or n-hexyl4-(diethylaminoacetylamino) 2 ethoxybenzoate. When the above procedureis followed but using. nstead of ethyl 4-(diethylaminoacetylamino) 2-ethoxybenzoate, ethyl 4-(3-diethylaminopropanoylamino)-2-ethoxybenzoate, ethyl 4-(4-diaeqm o 9.ethylaminobutahoylanfino) 2- ethoxybenzoate, ethyl 4-. (4-.diethylamino2; methylbutanoyh amino).-..21ethoxybenzoate.- or: ethyl 4-. (2' -meth1yl 1 piperidyl) acetylamino]-2-ethoxyb.enzoate, there is obtained,respectively, 4-(3-..diethy1- aminopropanoylamino).-2rethoxybenzoic.acid, 4- (4 diethylaminobutandylamino) 2-ethoxybenzoic acid,4-(4-diethylamino-z methylbutanoylamino) -2-ethoxybenzoicacidor"4-[(2-methyl-1- piperidyl) acetylamino] -2-ethoxylpenzoic acid.

4 (diethylaminoacetylamino) -'2-n-butoxyben zoic acid was preparedfollowing the above procedure but using 24.8 g. of ethyl-4-(diethylaminoacetylamino)-2n-butoxybenzoate, 6.0 g. of potassiumhydroxide,'200 ml. of ethanol and 100 m1. (if water. The product, in theform of. its hydrochloride addition salt, melted at 205'.4'-206.0.- C.(con), with decomposition, when recrystallized from dilute "aqueous'hydrochloric acid with de colorization using-decoloi izing charcoal.

Found: N, 7.65. Whenthe above-procedure i followeclbutusing theappropriate lower: alkyl '4-(tertiary-amiho acetylamino)-2-alkoxybenzoate, there is obtained the following compounds:4-[(1-piperidyDacetylamino] 2-n-propoxybenzoic acid; 4- [(1 pyrrolidyl)acetylamino] -2 n-butoxybenzoic acid; 4-[ Z-methyl-l -pyrr ol-idyl)acetylaminol -2- n-propoxybenzoic acid;4-[(2,5-dimethyl-1-pyrrolidyl)acetylarnino]-2-n-butoxybenzoic acid; 4-E26 --'diinethyl=- ipi peri'dyllacetylamino1-2450- bu toxybnzoic -acids4- (4'mor:pholinyl) acetylaminol-Z-n-hexoxybenzoic acid;l-(di-n-butylaminoacetylamino)- -2amethoxybenzoic acid; 4-(dimethylaminoacetylamino 2. isobutoxybenzoic acid; 4- 1.- p i peri dyl)acetylaminol-Z-nhexoxybenzoic acid.

4 (diethylaminoacetylami-no) 2 benzyloxybenzoic acid was obtainedfollowing the above procedure but using 33. 3;.-g. of ethyl4-(diethylaminoacetylamino)-2-benzyloxybenzoate, 7.3 g. of potassiumhydroxide, 200ml. of ethanol and new, :-.S,-Hl, il r duct .6. eig. salt,melted. at'1 80.'7 18'2.0 C. when recrystallized once from a mixture. of350. ml. oi water and 30 ml. of concentrated hydrochloric acid withdecolorization i1sing""decolorizing charcoal, and twice from absoluteethanol. It was dried at 100 C. in vacuo for eight hours. 4

Anal.-Calcd. for C2QH24N2Q4IC1I Cl, 9.02; N, 7.13. Found: Cl, 8.90; N,7.34.

4 (diethylaminoacetylaminq) 2 benzyloxybenzoic acid is also obtainedfollowing the above procedurebut using, in place of ethyl'i-idiethy-laininoacetylamino) 2 benzyloxybenzoate; the corresponding 7methyl: 4- diethylami-noacetylamino) -2-benzylo ;yben z oate, n-propyl4-(diethylaminoacetylamino) 2 benzyloxybenzoate, nbutyl 4-diethylaminoacetylainino) -2-benzyloxybenzoate, isobutyl4-(diethylaipinoacetylamino)- 2-benzyloxybenzoate, n-amyl 4-('diethylaminoacetylamino) -2-benzyloxybenzoate or n-hexyl 4-(diethylaminoacetylamino) 2- benzyloxybenzoate.

When-the above-procedureis.followed-but using, in place of ethyl4-(diethylaminoacetylamino)- Z-benzyloxybenzoate, ethyl. 4-[-(1-piperidyl) acetylamino]-2benzyloxybenzoate. ethyl 4-[3-(1-pyrrolidyl)propanoylamino] 2 benzyloxybenzoate or ethyl 4-[4-(4-morpholinyl)-3-methy1- butanoylamino]-2-benzyloxybenaoate, thereis obtained, respectively, 4[(1--'piperidyl)acetylamino]-2-benzy1oxybenzoicacid, 4-[3-(1-pyr- 1'0roiidyl .propano laminol-.- 2; ben yloxyben o c acid or 4- [4-(4-morpho1iny1) -3-methylbut anoyl' amino].-.2kbfinzyloxybenzoic acid.

. ic l tcwylmmm--?*-q mu 1. W. w w? Me inda c mmand are. p ep re r m.the. om t tiar-y' arninqalkanoylam' 0)-.2

- oalkaee leminqt-%fib%zr ezs beezoieaci e reparation is carried-outpref -e rably bytreating: the aci w th. aibelpsenatinsa ent. re er blythl d nto. ra dly sti r d; H ncentratec ammo. em

erat o mt xt rewasr tl r dior a add.- 0..-; ttest-1 .1 nma the enzene ae separ ted and the aa eeuala erwas zs reetcdtW 'be z na ae pmbimd enzen-la r. c xtr ct e r ed. decclorfizqdr e h moalz and; ramratedtedmness-inir 0,: t ereb me d n a ol d materia Eor a aly t samp e o t s olWasrecr s ed m ce firqm" benzme-n-h X-ene 40- i 1.. ethanolhe. su t neteac ieis y a acety a o .-.2.-.eth9xye Zamid "mQ 4i534i; .$--133 @012 wn. r ,d at; 9.07 6- v uo. fewest-, hour An. TGa Qd Q H2 Ns. .1 N34,. 4-F UD-diZ-"NBA, 4.90.

NBA stands for: basic amino nitrogen as determined by titration withperchloric acid. in. glacial aceticiacidjsolution.

4 (diethylaminoacetylamino) 2 etho amide wefi... 2qi e tedidtq i s. mehl i 'qa'sa t a i le e eth l, min a rsthoxrben mide was. r

I ia wa hea w th. en I 29% by 0. 291mg h re se rat d. hlQ email-ic d.-Th r t l ine. product. qllej teq wash d. l ab ol te ether an sr all zed9atmm. sep panohe hr ac eta- 51 e.- immab q uie amnelhre thus. qbpai qend th 9a am n0, re h .b .c e.

Following the abov p ocedure t laman p ace 0i 4:. di thy m neacet amino2: i129; yb nzoic. acidhydrochlor de. e. of 41- ii fihqlr min a tyaminoii m-bHtQXY Q ZQ Q acid b drochloride. and. as; othe om onents rhere: tipnymixtzure, 22kg ofspy t dinegzqb. 11 Q drybenzene and 'h ilg.of thionyl; chloride, there-was obtained,- 4; (diethylaminoacetylamino1.2; n.-. butoxyben'zamide, M: P..--l5 4;0+ 1f1,5 .2 G. (con); 75.when-recrystallized:twigeifrom beB }e.-n.-hexane= AnaZ.-Calcd. forC11H27N303! N, 13.07. Found: N, 13.34.

4- (diethylaminoacetylamino) -2-n-butoxybenzamide hydrochlorids,obtained as above by following the procedure used in preparing4-(diethylaminoacetylamino) -2-ethoxyzenzamide hydrochloride, melted at228.6230.2 C. when recrystallized once from absolute ethanol-ether andonce from absolute ethanol-isopropanol.

AnaZ.Calcd. for C17H2'7N3O3.HC1I N, 11.74; Cl, 9.91. Found: N, 11.59;Cl, 9.73.

When the above procedure is followed but using the appropriate4-(tertiary-aminoalkanoylamino) -2-ethoxybenzoic acid, either in freebase form or in form of its hydrochloride salt, in place of 4-(diethylaminoacetylamino) -2-ethoxybenzoic acid hydrochloride, there isobtained the following compounds: 4 (3 diethylaminopropanoylamino)2-ethoxybenzamide; 4- (4-diethylaminobutanoylamino) 2 ethoxybenzamide;4-(4-diethy1amino2-methylbutanoylamino) -2 ethoxybenzamide: 4-[Z-methyl-l-piperidyl) acetylamino] 2ethoxybenzamide; 4-[ (l-piperidyl)acetylamino] 2 n-propoxybenzamide; 4-[(1-pyrrolidyl) -acetylaminol-2-n-butoxybenzamide; 4[ (2- methyl-l-pyrrolidyl)acetylamino1-2-npropoxybenzamide; 4- 2,5-dimethyl-l-pyrro1idyl) acetylamino]-2-n-butoxybenzamide; 4-[ (2,6-dimethyll-piperidyl) acetylamino]-2-isobutoxybenzamide; 4-[ (4-morpholinyl) acetylamino] 2 nhexoxybenzamide; 4- (di-n-butylaminoacetylamino) 2- methoxybenzamide; 4-(dimethylaminoacetylamino) -2isobutoxybenzamide; and 4-[(1piper idyl)acetylaminol -2-n-hexoxybenzamide.

4 (diethylaminoacetylamino) 2 benzyloxybenzamide was prepared followingthe above procedure but using 19.1 g. of4-(diethylaminoacetylamino)-2-benzyloxybenzoic acid hydrochloride, 4.4g. of pyridine, 200 ml. of dry benzene, 6.4 g. of thionyl chloride and amixture of 300 ml. of concentrated ammonium hydroxide and 300 ml. ofwater. The product, 4-(diethylaminoacetylamino) -2-benzyloxybenzamide,when recrystallized once from ethyl acetate-n-hexane and once fromdilute ethanol, formed cottony white needles,

M. P. 137.6-l38.0 C. (cor.) when dried at 90 C.

in vacuo for seven hours.

AnaZ.-Calcd. for CzoHzsNsOs. NBA, 3.94. Found: NBA, 4.10.

This amide was converted into its corresponding hydrochloric acidaddition salt by dissolving it in ethyl acetate and treating thesolution with an excess of 20% ethereal hydrogen chloride. The productseparated as a gum, which crystallized when the solvent was removed bydecantation and the gummy material was triturated with a hot mixture ofisopropanol and ethyl acetate. The mixture was diluted with ethylacetate, cooled and the resulting precipitate collected. The precipitatewhen recrystallized from absolute ethanol-ethyl acetate yielded 4-(diethylaminoacetylamino) 2 benzyloxybenzamide hydrochloride, M. P.199.2-l99.6 C. (cor.) (dried for seven hours at 90 C. in vacuo).

AnaZ.-Calcd. for C20H25N3O3.HC12 N, 10.72; Cl, 9.05. Found: N, 10.56;Cl, 8.85.

When the above procedure was followed but using, in place of4-(diethylaminoacetylamino)- 2-benzyloxybenzoic acid hydrochloride,4-[(1- piperidyl) acetylaminol -2-benzyloxybenzoic acid, 4-[3-(l-pyrrolidyl) propanoylamino] 2 benzyloxybenzoic acid or4-[4-(4-morpholinyl) 3- methylbutanoylaminol-2benzyloxybenzoic acid,ortheir hydrochlorides, there is obtained, respecoxybenzamide, 4 [3 (1pyrrolidyDpropanoylamino] -2-benzyloxybenzamide or4-[4-morpholinyl)-3-methylbutanoylamino] 2 benzyloxybenzamide.

I claim: 1. A compound having the formula NHCO-X-NRRr c o o R; whereNRR1 is a (lower alkylated)-1-piperidyl radical and R2 and R3 are eachlower alkyl radicals.

3. A lower alkyl 4-tertiary-aminoacetylamino- 2-alkoxybenzoate havingthe formula NBC 0 OHzNRR NBC 0 C HzNOower alkyl);

COOR:

where R2 and R3 are each lower alkyl radicals.

5. A lower alkyl 4-diethy1aminoacetylamino-2- alkoxybenzoate having theformula where R2 and R3 are each lower alkyl radicals.

6. A lower alkyl 4-tertiary-aminoacetylamino- 2-benzyloxybenzoate havingthe formula NHC O CHaNRRn OCHzCaH NHC OCHzNRRz ,i 00R: where NRRI is a:2-methyl' 1-pi11eridyl. radical and R3 is a lower alkyl radical.

8. A lower alkyl 4 diaIkyIaminOacetylamino-2- benzyloxybenzoate havingthe'f'ormula lFIHC 0 o HgNaower alk l oemonm where R is a lower alk'ylradical.

9. A lower alkyl 4-diethylaminoacetylainino 2-' benzyloxyb'enzoatehaving the formula NHC ooHiNwz'Hm 0 where R3 is a lower alkyl radical.

10. A process of preparing a compound having the formula NHC o-X-NRR,

C 0 OR;

where X is a lower alkylene radical, NRR1 is a member of the groupconsisting of lower dialkylamino, l-piperidyl, (loweralklated)-1-piperidyl, l-pyrrolidyl, (lower alkylated)-1-pyrrolidyl and4-morpholinyl, R2 is a member of the group con- 0 sisting of a loweralkyl radical and the benzyl radical and R3 is a lower alkyl radical,which comprises treating the corresponding lower alkyl 4-amino-2-substituted-benzoate with a haloalkanoyl halidehaving theformula halogen-X-CO- halogen and treating the resulting lower alkyl 4(haloalkanoylamino) 2 substituted benzoate with a secondary amine havingthe formula HNRR1.

11. A process of preparing a compound having the formula 314 weresecondary amine having the formula HNRRi. Y

12." A process ofpreparing a' compoundhaving the'formula NH6 6 omiiitmwhere NRR1 is a 2-methyl-1-piberidylradical and R2 and R3 are each loweralkyl radicals, which comprises treating the corresponding lower alkyl4-amino-2-alkox'ybenzoatewith a haloacetyl halide and treating theresulting lower alkyl 4- (haloacetylamino) -2 -alkoXybenzoate with2-methylpiperidine.

A processor preparing-aeempoumaaviiig the formula where R2 andRy-areeaehuower alkyl radicals, which comprises treating thecorresponding lower alkyl 4-amino-2alkoxybenzoate with a haloacetylhalide and treating the resulting lower alkyl 4- (haloacetylamifio)2=alko ybenzoate with a secondary amine having the formula HN (loweralkyDz.

14. A process of preparing a compound having the formula OORa where R:and R3 are each lower alkyl radicals, which comprises treating thecorresponding lower alkyl 4-amino-2-alkoxybenzoate with a haloacetylhalide and treating the resulting lower alkyl 4- (haloacetylamino)-2-alkoxybenzoate with diethylamine.

15. A process of preparing a compound having the formula mrooommmOCHaCeHs OORa where NRR1 is a (lower alkylated) -1-piperidyl radical andR3 is a lower alkyl radical, which comprises treating the correspondinglower alkyl 4- amino-2-benzyloxybenzoate with a haloacetyl halide andtreating the resulting lower alkyl 4-(haloacetylamino)-2-benzyloxybenzoate with a secondary amine having theformula HNRR1.

16. A process of preparing a compound having the formula NHCOCIEHNRR]OCHzCaHu OOR:

where NRR1 is a 2-methyl-l-piperidyl radical and R3 is a lower alkylradical, which comprises treating the corresponding lower alkyl 4-amino-2-benzyloxybenzoate with a haloacetyl halide and treating the resultinglower alkyl 4-(haloacetylamino) 2 benzyloxybenzoate with 2methylpiperidine.

17. A process of preparing a compound having the formula IIIHC OCHnNGower alkyl):

OCHaCsHs COOR:

where Re is a lower alkyl radical, which comprises treating thecorresponding lower alkyl 4-amino- 2-benzyloxybenzoate with a haloacetylhalide and treating the resulting lower 4- (haloacetylamino)-2-benzyloxybenzoate with a secondary amine having the formula I-INGoweralkyl) 2.

18. A process of preparing a compound having the formula NHG OOHaN(OaHa)2 OCHaCeHs where R3 is a lower alkyl radical, which comprisestreating the corresponding lower alkyl 4-amino-2-benzyloxybenzoate witha haloacetyl halide and treating the resulting lower alkyl 4-(haloacetylamino) -2-benzyloxybenzoate with diethylamine.

19. A 4 dialkylaminoacetylamino 2 alkoxy benzamide having the formulaIIIHC O C HaNOower alkyl):

ONHQ

where R2 is a lower alkyl radical.

20. A 4 diethylamino acetylamino 2 alkoxybenzamide having the formulaNHGOCHzN(CaHa)z C ONH:

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 619,549 Einhorn Feb. 14, 1899 1,903,927 Legerlotz Apr. 18,1933 OTHER REFERENCES Moore: J. of Amer. Pharm. Association, vol. 33,July 1944, pp. 193-204.

1. A COMPOUND HAVING THE FORMULA